sign in sign up
<<
Home , Factor V

JOURNAL AVAILABLE AT RADIOLOGYUPDATE.ORG

Factors contributing to the hypercoagulable state. Clinical case of intracardiac and massive pulmonary embolism Julius Vidikas1, Evelina Gudavičiūtė², Matas Kalinauskas²

1Lithuanian research center of health sciences ²Faculty of Medicine, Academy of Medicine, Lithuanian University of Health Sciences, Eiveniu str. 2, LT-50009 Kaunas, Lithuania

ABSTRACT , or hypercoagulable state, can cause various thrombotic events. It occurs due to inherited and/or ac- quired factors. Inherited risk factors, such as , , prothrombin, S and C , have been associated with increased presence of and some suggest an increased arterial thrombosis incidence as well. Acquired risk factors are found more often than inherited. The most prominent acquired risk factors include atrial fibrillation, malignancy, sepsis, obesity, diabetes mellitus, antiphospholipid syndrome and COVID-19 infection. All of these risk factors alone can cause thrombotic events, but most of the time thrombosis occurs due to multifactorial interaction of various established risk factors and patients’ overall well-being. With this article we present a case report of intracardial thrombosis in a patient with atrial fibrillation and a brief literature review of the causes of hypercoagulability.

Keywords: Thrombophilia, thrombosis, tomography.

bus formation. In current times inherited throm- INTRO bophilia can be classified according altering Thrombophilia, or hypercoagulable state, refers mutations, which consists of – loss of function to a blood disorder, which can increase clot- and gain of function [4]. The former involves ting and formation. This was known inhibitor decrease and it includes since 1856, when Virchow introduced his triad antithrombin (AT), (PC) and protein of mechanisms for thrombosis, which remained S (PS), while the latter incorporates coagulation relevant to modern times [1]. Nowadays, throm- factor increase – the most prominent being fac- bophilia can be classified to inherited or acquired. tor V Leiden (FVL) and prothrombin G20210A Specific genetic mutations have been identified, (PT) [4, 5]. FVL and PT are accounta- which can greatly affect the blood coagulation ble for 50–70% of inherited thrombophilia that and coagulation factor function. There are also has been diagnosed [2]. However, AT, PC and PS various acquired diseases that can increase the can contribute to severely greater thrombosis, risk of either venous or arterial thrombus for- even if they are less frequent [2,4]. Blood group mation [2]. Thrombophilia can predispose var- ABO may also plays a role in thrombophilia. It ious thrombotic events, however thrombosis or has been reported that people with ABO blood thromboembolisms are often multifactorial [3]. group tend to have an increased risk of venous This report analyses the most common inherited thromboembolism [2,6,7]. and focuses on the various dis- eases that can have a risk for hypercoagulability. FACTOR V LEIDEN

INHERITED RISK FACTORS FOR HYPER- FVL may depict up to 50% of diagnosed hered- COAGULABILITY itary thrombophilias [4]. Although being the more prevalent, it tends to pose a weaker risk Inherited thrombophilia is a genetically deter- for thrombus formation [2]. Heterozygote carri- mined tendency of venous and/or arterial throm- ers of this trait tend to have a 5-fold higher risk

34 RADIOLOGY UPDATE VOL. 5 (8) ISSN 2424-5755

for VTE disease. For homozygotes this risk can of 55.6% was reported in retrospective study of reach up to 50-fold higher [8]. Furthermore, 18 pregnancies of women with AT, however pa- women with FVL can have an up to 3-fold great- tients treated with anticoagulation were seen to er risk for miscarriage and various gynecologi- have fewer complications [16]. Although, AT is cal complications during pregnancy, however associated with higher venous thrombosis risk, the rate of successful delivery is still high [9]. A arterial thrombosis risk seems to be unaffected study in Argentina concluded that FVL might – meta-analysis of 12 studies found no statistical have a significant effect on fetal growth retarda- significance with AT and arterial ischemic stroke tion, while PT mutations were found insignifi- cases [9]. cant compared to control study [10]. PT is the second most common inherited thrombophilia. AND C MUTATIONS Carriers of G20210A mutation have an increased Similar to AT deficiency, PC and PS mutations plasma prothrombin of 30% for heterozygous are less frequently found in general population, and 70% for homozygous [8]. In general popula- but both are strong risk factors for thrombosis tion the prevalence for PT mutation is up to 4% [17]. PC and PS role in coagulation is associated with Caucasians being the most affected race [4]. with one another – activated form of PC is a nat- Comparing PT and FVL mutations for people of ural and PS is it co-factor [2]. PC 30 years and younger, PT tends to have a higher deficiency can be asymptomatic or can lead to risk of developing VTE than FVL – 0.44% and extensive thrombosis and disseminated intravas- 0.25% respectively [11]. Both FVL and PT in- cular coagulation [4]. It is reported that people crease the risk for thrombotic events in women with this mutation have a 2-3 times greater risk who use oral contraceptives. Women with FVL of experiencing first episode of VTE than those and PT mutations, who use oral contraceptives who have FVL or PT mutations [18]. About 50% are, respectively, at 35 to 99 times and 16 times of PC mutation carriers experience a thrombotic greater risk than non-carriers who don’t use OCs event as early as 45 years of age [4]. Homozy- [12]. A prospective study of 354 elderly patients gous PC deficiency can also cause a severe life found that FVL and PT were not associated with threatening condition – ischemic necrosis of ex- VTE recurrence [13]. A recent meta-analysis con- tremities, which is due to dermal vessel throm- cluded that both FVL and PT, regardless of zygo- bus manifestation [2]. PC and PS are found only sity, were found in significantly more arterial is- about 0.1-0.2% in general population [4,18]. PS, chemic stroke cases than control studies [14]. however, is more likely to be detected in Asians [8]. Homozygous or double heterozygous PS de- ANTITHROMBIN DEFICIENCY ficiency is very rare and symptoms of this muta- Antithrombin deficiency may be relevant in tion is resembling the same PC deficiency mu- about 1% of VTE cases and even less so in arteri- tations [8]. PS defect has been associated with a al thrombosis cases [15]. However, AT is linked 10-fold greater risk of VTE [19]. Both PC and with a high risk of thrombosis, with spontane- PS in the latest meta-analysis were found to be ous VTE occurring in 60% of cases [4]. With- statistically significantly associated with arterial out anticoagulation therapy the risk for VTE ischemic stroke [5]. occurrence is approximately 10.5% per year. BLOOD GROUP ABO Prescribing long-term reduces this incidence significantly, but still about 2.7% It is well established that people with ABO blood of patients will experience recurrent thrombosis group tend to experience thrombotic events more [8]. AT mutation in pregnant women can be re- frequently. The thought behind it is that VTE and sponsible for first time VTE development up to other thrombotic developments are associated 31% if there are no other risk factors associat- with ABO because , which ed with thrombosis and up to 50% if there are is about 25% higher in ABO groups, and factor risk factors present [4]. Poor pregnancy outcome VIII (FVIII) plasma levels [20]. A recent retro- 35 JOURNAL AVAILABLE AT RADIOLOGYUPDATE.ORG

spective study in China concluded that patients zation are associated with obesity, which is an with non-O blood types experienced statistical- additional prothrombotic risk factor [30]. The ly significantly more VTE episodes than control mechanism of the obesity related hypercoag- group [21]. ABO blood groups are linked with ulability includes a pro-thrombotic state sec- 2.6-fold greater risk for occurrence of VTE, with ondary to chronic inflammation and decreased blood group A being the most dominant in this clot breakdown via inhibition of the fibrinolytic risk [8]. A study in Denmark established that pathway [31]. The proinflammatory and lesser non-O was the most prevalent risk fibrinolytic response indicates that obesity might factor for VTE and was significantly associated be exacerbated by dysregulated expression and with VTE manifestations [22]. Moreover, people secretion of adipokines and microRNAs, which with non-O blood type accompanied with in- later increase the risk of thrombosis [31]. Obese herited thrombophilia have a risk of VTE up to individuals have shown increased circulating 23.2-fold greater than control cases [2]. levels of von Willebrand factor (VWF), , factor VII and VIII, and , caus- ing a mild to moderate hypercoagulable state ACQUIRED RISK FACTORS FOR HYPER- [32]. A case-control study with patients aged COAGULABILITY 18-65 years attending outpatient venous throm- boembolism (VTE) clinics, evaluated that pro- longed work and computer related immobility ANTIPHOSPHOLIPID SYNDROME (APS) increased risk of VTE in adults who were seated One of the acquired risk factors for hypercoag- for at least 10 hours/day, including at least 2 con- ulation is the antiphospholipid syndrome (APS) secutive hours without getting up [30]. whereat antibodies are directed against natural constituents of cell membranes, the phospholip- SEPSIS ids [23]. Antiphospholipid syndrome is a system- Sepsis is a rather commonly acquired hyperco- ic autoimmune disease manifests by arterial or agulable state in patients with severe infection. venous thrombosis [24]. Although antiphospho- While this condition persists, coagulation system lipid antibodies (APLA) occur in 3 to 5% of the is greatly influenced and can result in dissemi- population, they are dangerous because of their nated intravascular coagulation (DIC), which in ability to cause arterial or venous thrombosis, turn can lead to and/or multiple organ even fetal loss [23]. Common clinical manifes- failure [33]. Approximately 50-70% of patients tations of APS include stroke, venous thrombo- with sepsis are showing signs of significant co- embolism, recurrent early miscarriages and late agulation effects, but only a third will adhere to pregnancy losses [25,26]. The presence of APLAs the criteria for DIC [34]. Hypercoagulability in is a significant factor for thrombotic events, but sepsis is likely to have numerous pathogenetic it is noticed that secondary triggers, such as in- mechanisms involved and that is the most like- fections, immobility are usually necessary for the ly reason why single substance therapies have progression of the syndrome [27]. APLA is pos- not contributed to better outcomes [34]. During itive when positive tests repeat ≥ 12 weeks apart sepsis pro-inflammatory cytokines and chemok- [28]. According to Sidney criteria, five tests have ines are interacting with the natural coagulation to be taken: the lupus anticoagulant, anticardi- process, resulting in impairment of olipin antibodies IgG or IgM and aβ2GP1 IgG and tissue-factor activation. This interaction in or IgM [28]. APLA can also occur secondarily to turn enhances generation and - other diseases like collagen vascular disease or ogen to fibrin conversion. interact with drugs like phenytoin, cocaine [23, 29]. vessel endothelium and thrombin resulting in OBESITY activated platelets circulating and binding with conversed fibrin, which can result in micro- Sedentary lifestyle and protracted immobili- vascular clot formation [35]. Moreover, it been

36 RADIOLOGY UPDATE VOL. 5 (8) ISSN 2424-5755

known that -activating factor is excreted and inflammation among patients with diabetes during inflammation, which accelerates the pro- mellitus [44]. Hypercoagulable state is a conse- cess even further [34]. Furthermore, activated quence of these vascular abnormalities [44-46]. platelets express protein P-selectin, which affects Hyperglycemia leads to a development in oxida- monocytes increasing tissue factor secretion tive stress, which may cause increased markers and pro-inflammatory cytokines and chemok- of inflammation, endothelial dysfunction, de- ines [35]. Treatment of this condition has been creased adiponectin [44,46]. Also, it was noted, focused on reinforcing natural anticoagulation that VWF, IL-6, TNF-α, D-dimer and plasmino- pathways with antithrombin concentrate and re- gen activator inhibitor-1 (PAI-1) are higher in combinant human activated protein C. However, diabetic patients [44,47]. even though these methods have promising re- sults in restoring normal coagulation states, they MALIGNANCY haven’t shown to improve clinical outcomes of Hypercoagulable state can also be induced by patients [36]. tumor cells [48-50]. One of the mechanisms is COVID-19 that tumor cells produce fibrinolytic substances and inflammatory cytokines such as TNF-alpha, The hypercoagulable state is also observed in IL-1 and IL-6 and they develop blood thickening the presence of Covid-19 [37-40]. One of the [48,49]. Malignancy can also cause hypercoagu- mechanisms is based on increased VWF expres- lability because of inflammation, anomalous pro- sion in Covid-19 patients [37,40]. In the case tein metabolism and stasis [48]. It was noticed, of damaged endothelium, platelets may adhere that tissue factor (TF) and cancer pro-coagulant more easily to VWF on dysfunctional or dam- (CP) are being released which can cause plaque aged endothelium [37]. When VWF adheres to destabilization and hewing of factors X to Xa, the endothelium, platelets are easily activated which results in the formation of thrombin [49]. by like collagen, that may induce im- Also it should be considered, that stroke can be munothrombosis through the immunothyros- associated with cancer because of hypercoagula- ine (ITAM) receptor GPVI [37]. Excretion of ble state and it was noted, that D-Dimer levels adenosine diphosphate (ADP) and synthesis of and fibrin degradation products are higher [50]. thromboxane A2 (TxA2) supports platelet ac- tivity through thromboxane receptor (TR) and ATRIAL FIBRILLATION purinergic receptors (P2Y) [37]. There is also a hypothesis, that the renin-angiotensin system Atrial fibrillation (AF) is one of the most com- (RAS) may be involved in the pathophysiology mon continuous cardiac arrhythmias which is of COVID-19 [42]. When angiotensin II/angi- associated with hypercoagulable state [51-53]. It otensin I is activated, aldosterone is being re- was noticed in the meta-analysis, that high levels leased, which upregulates protein-C receptors in of circulating hemostatic markers such as PF- human vascular endothelium [42]. These recep- 4, BTG, P-selectin, D-dimer, fibrinogen, TAT, tors are affiliated with prothrombotic state [43]. F1+2, AT-III, and VWF were associated with AF Also, it was noted that D-dimer, fibrinogen deg- [51]. In this meta-analysis were described signif- radation products (FDP) and fibrinogen (FIB) icantly higher coagulation activation markers, values were undoubtedly elevated, meanwhile including plasma D-dimer, fibrinogen, throm- antithrombin (AT) was decreased [41]. Further- bin-antithrombin (TAT), prothrombin fragment more, anticipating of D-dimer and FDP can be 1+2 (F1+2), and antithrombin- III (AT- III) in used to monitor Covid-19 progression [41]. patients with AF than in control group [1]. Also, DIABETES MELLITUS the endothelial dysfunction marker VWF was higher in AF patients [51]. In another article it Vascular complications are frequently provoked was noted, that prothrombotic state in atrial fi- by endothelial dysfunction, hypercoagulability brillation is mostly driven by inflammation and

37 JOURNAL AVAILABLE AT RADIOLOGYUPDATE.ORG

the release of various growth factors [52]. During CLINICAL CASE the inflammation, IL-6 boosts platelet produc- tion and sensitivity to thrombin, triggers tran- 76 years old female patient came to admission scription of fibrinogen, and is linked to endothe- complaining about a month-long shortness of breath at rest. Patient with anamnesis of heart lial activation and damage [52]. Meanwhile, failure, chronic atrial fibrillation, claimed to con- vascular endothelial growth factor is heightened suming , Spironolactone, Torazemide, in persistent and permanent atrial fibrillation, Bisoprolol, Zofenopril. with an interrelated increase in TF [52]. Anoth- Blood pressure: 143 mm [Hg] / 82 mm [Hg], er study highlighted D-dimer because its values pulse: 100 rpm. may be associated with the appearance of atrial SPO2: 94%. The patient conscious, focused. He- thrombosis, might predict primary negative out- modynamics stable, cardiac arrhythmia. Breath- comes and death in patients with AF, and also ing in the lungs is vesicular, without corpuscles. might be a practical guideline for assessing the Abdomen soft, painless. No peripheral edema. degree of hypercoagulability of AF patients after ECG – tachycardia and atrial fibrillation. cardioversion [53].

CTA. Axial plane. No. 2. Massive thrombus is seen in the left main pulmonary artery (green CT topogram. Enlarged heart. arrow).

CTA. Axial plane. No. 3. Thrombus in right CTA. Axial plane. No. 4. Thrombus in right atrial appendage. (Green arrows). atrial lateral side, enlarged atrial space. (Green arrows).

38 RADIOLOGY UPDATE VOL. 5 (8) ISSN 2424-5755

CTA. Axial plane. No. 5. Enlarged diameter of CTA. Axial plane. No. 5. Contrast regurgitation pulmonary trunk indicating pulmonary hyper- to inferior v. cava and hepatic veins indicating tension. right heart chambers overuse. (Green arrow).

CTA. Axial plane. No. 6. Thin free fluid layer in CTA. Axial plane. No. 7. Thin fluid layer in per- right pleural space. (Green arrow). icardial space. (Green arrow).

39 JOURNAL AVAILABLE AT RADIOLOGYUPDATE.ORG

Laboratory examination results Test Result Normal range (%) 47 70 - 130 International Normalized Ratio 1.45 0.9 – 1.2 Activated partial thromboplastin time (APTT) (s) 31.7 26.3 – 40.3 D-dimer (mg/l) >4.00 0 – 0.5 Troponin I (ng/l) 15 0 – 10 MCHC (g/l) 334 320 – 360 PLT (µU/ml) 192 150 – 400 MPV (fl) 10 6 – 11 PDW (%) 13.7 11 – 18 PCT (l/l) 0.0019 0.0015 – 0.004 WBC (µU/ml) 9.3 4 – 10 LYM# (µU/ml) 1.35 1 – 4 RBC (µU/ml) 5.03 4.1 – 5.1 HGB (g/l) 152 120 – 150 HCT (l/l) 0.455 0.35 – 0.47 MCV (fl) 90.4 82 – 98 MCH (pg) 30.2 27 – 31 LYM% (%) 14.7 22 – 43 NEU % (%) 76.3 42 – 68 EOS% (%) 0.8 1 – 4.9 BAS% (%) 0.5 0.1 – 0.9 MON% (%) 7.7 4 – 12 LIC% (%) 0.6 0 – 3 MON# (µU/ml) 0.71 0.2 – 1 NEU# (µU/ml) 7.05 2 – 7.5 EOS# (µU/ml) 0.07 0.04 – 0.48 BAS# (µU/ml) 0.04 0.01 – 0.24 LIC# (µU/ml) 0.05 0 – 0.35 RDW- CV (%) 14 11 – 17 RDW-SD (%) 47 37 – 49 P-LCR 28.1 18 – 50 P-LCC 54 44 – 140 Hemolysis + Potassium (mmol/l) 4.1 3.5 – 5.2 Sodium (mmol/l) 138 135 – 145 Blood glucose (mmol/l) 6.28 3.9 – 6.4 Urea (mmol/l) 6.5 3.5 – 7.2 Creatinine (µmol/l) 77.3 45 – 84 CRP (mg/l) 8.3 0 – 5

- X- ray was not informative, dilatation of heart was seen. - Computer tomography angiography was performed with indication: pulmonary embolism.

40 RADIOLOGY UPDATE VOL. 5 (8) ISSN 2424-5755

After the diagnosis of massive pulmonary em- bolism and intracardial thrombosis patient was hospitalized to intensive care department of car- diology for further treatment.

CONCLUSION

This case report is a reminder for health care workers that hypercoagulable state can be caused by many acquired and hereditary factors. By hav- ing this in mind, doctors can notice risk factors and diagnose hypercoagulability sooner which can prevent life threatening outcomes. In our case main factors for hypercoagulable state were atrial fibrillation and heart failure, however case it self-showed, that patient toler- ated massive thrombosis with minor symptoms. Considering imaging examinations CTA is still one of the most accurate test for hypercoagulable complications diagnosis.

41 JOURNAL AVAILABLE AT RADIOLOGYUPDATE.ORG

REFERENCES 16. Sabadell J, Casellas M, Alijotas-Reig J, Arellano-Rodrigo E, Cabero L. Inherited antithrombin deficiency and pregnancy: maternal and fetal outcomes. Eur J Obstet Gynecol Reprod Biol. 1. Bagot CN, Arya R. Virchow and his triad: a question of attri- 2010 Mar;149(1):47-51. doi: 10.1016/j.ejogrb.2009.12.004. bution. Br J Haematol. 2008;143(2):180-190. doi:10.1111/j.1365- 2141.2008.07323.x. 17. Wong P, Baglin T. Epidemiology, risk factors and sequelae of venous thromboembolism. Phlebology. 2012;27 Suppl 2:2-11. 2. Campello E, Spiezia L, Adamo A, Simioni P. Thrombophilia, doi: 10.1258/phleb.2012.012s31. risk factors and prevention. Expert Rev Hematol. 2019;12(3):147- 158. doi:10.1080/17474086.2019.1583555. 18. Middeldorp S. Inherited thrombophilia: a double-edged sword. Hematology Am Soc Hematol Educ Program. 2016 Dec 3. Stevens SM, Woller SC, Bauer KA, et al. Guidance for the eval- 2;2016(1):1-9. doi: 10.1182/asheducation-2016.1.1. uation and treatment of hereditary and acquired thrombophil- ia. J Thromb . 2016;41(1):154-164. doi:10.1007/ 19. Undas A, Góralczyk T. Direct Oral Anticoagulants in Patients s11239-015-1316-1. with Thrombophilia: Challenges in Diagnostic Evaluation and Treatment. Adv Clin Exp Med. 2016 Nov-Dec;25(6):1321-1330. 4. Hotoleanu C. Genetic Risk Factors in Venous Throm- doi: 10.17219/acem/65853. boembolism. Adv Exp Med Biol. 2017;906:253-272. doi: 10.1007/5584_2016_120. 20. Dentali F, Sironi AP, Ageno W, Turato S, Bonfanti C, Frattini F, Crestani S, Franchini M. Non-O blood type is the commonest 5. Aiach M, Alhenc-Gelas M, Borgel D, Emmerich J, Gandrille S, genetic risk factor for VTE: results from a meta-analysis of the Picard V. Mutations des protéines de la coagulation et thromboses literature. Semin Thromb Hemost. 2012 Jul;38(5):535-48. doi: [Coagulation factor mutations and thrombosis]. Med Sci (Paris). 10.1055/s-0032-1315758. 2006 Nov;22(11):985-9. doi: 10.1051/medsci/20062211985. 21. Sun X, Feng J, Wu W, Peng M, Shi J. ABO blood types associ- 6. Sun X, Feng J, Wu W, Peng M, Shi J. ABO blood types associ- ated with the risk of venous thromboembolism in Han Chinese ated with the risk of venous thromboembolism in Han Chinese people: A hospital-based study of 200,000 patients. Sci Rep. 2017 people: A hospital-based study of 200,000 patients. Sci Rep. 2017 Mar 6;7:42925. doi: 10.1038/srep42925. Mar 6;7:42925. doi: 10.1038/srep42925. 22. Sode BF, Allin KH, Dahl M, Gyntelberg F, Nordestgaard BG. 7. Wu O, Bayoumi N, Vickers MA, Clark P. ABO(H) blood Risk of venous thromboembolism and myocardial infarction as- groups and vascular disease: a systematic review and meta-anal- sociated with factor V Leiden and prothrombin mutations and ysis. J Thromb Haemost. 2008 Jan;6(1):62-9. doi: 10.1111/j.1538- blood type. CMAJ. 2013 Mar 19;185(5):E229-37. doi: 10.1503/ 7836.2007.02818.x. cmaj.121636. 8. Koenderman J.S., Reitsma P.H. Thrombophilia. InTech; Lon- 23. Senst B, Tadi P, Goyal A, et al. Hypercoagulability. [Updated don, UK: 2011. Inherited Thrombophilia: Past, Present, and Fu- 2020 July 8]. In: StatPearls [Internet]. Treasure Island (FL): Stat- ture Research. doi: 10.5772/26050. Pearls Publishing; 2020 Jan-. Available from: https://www.ncbi. 9. Kujovich JL. Factor V Leiden thrombophilia. Genet Med. 2011 nlm.nih.gov/books/NBK538251/. Jan;13(1):1-16. doi: 10.1097/GIM.0b013e3181faa0f2. 24. Bala MM, Celinska-Lowenhoff M, Szot W, Padjas A, Kacz- 10. Perés Wingeyer S, Aranda F, Udry S, Latino J, de Larrañaga marczyk M, Swierz MJ, Undas A. Antiplatelet and anticoagulant G. Inherited thrombophilia and pregnancy loss. Study of an Ar- agents for secondary prevention of stroke and other thrombo- gentinian cohort. Med Clin (Barc). 2019 Apr 5;152(7):249-254. embolic events in people with antiphospholipid syndrome. English, Spanish. doi: 10.1016/j.medcli.2017.12.019. Cochrane Database Syst Rev. 2020 Oct 12;10:CD012169. doi: 11. Bank I, Libourel EJ, Middeldorp S, Van Pampus EC, Koopman 10.1002/14651858.CD012169.pub3. MM, Hamulyák K, Prins MH, Van Der Meer J, Büller HR. Pro- 25. Miyakis S , Lockshin MD , Atsumi T , et al . International thrombin 20210A mutation: a mild risk factor for venous throm- consensus statement on an update of the classification criteria for boembolism but not for arterial thrombotic disease and preg- definite antiphospholipid syndrome (APS). J Thromb Haemost nancy-related complications in a family study. Arch Intern Med. 2006;4:295–306.doi:10.1111/j.1538-7836.2006.01753.x. 2004 Sep 27;164(17):1932-7. doi: 10.1001/archinte.164.17.1932. 26. Tektonidou MG, Andreoli L, Limper M, Amoura Z, Cervera 12. Gialeraki A, Valsami S, Pittaras T, Panayiotakopoulos G, R, Costedoat-Chalumeau N, Cuadrado MJ, Dörner T, Ferrer-Ol- Politou M. Oral Contraceptives and HRT Risk of Thrombo- iveras R, Hambly K, Khamashta MA, King J, Marchiori F, Meroni sis. Clin Appl Thromb Hemost. 2018 Mar;24(2):217-225. doi: PL, Mosca M, Pengo V, Raio L, Ruiz-Irastorza G, Shoenfeld Y, 10.1177/1076029616683802. Stojanovich L, Svenungsson E, Wahl D, Tincani A, Ward MM. 13. Méan M, Limacher A, Stalder O, Angelillo-Scherrer A, Alber- EULAR recommendations for the management of antiphospho- io L, Fontana P, Beer HJ, Rodondi N, Lämmle B, Aujesky D. Do lipid syndrome in adults. Ann Rheum Dis. 2019 Oct;78(10):1296- Factor V Leiden and Prothrombin G20210A Mutations Predict 1304. doi: 10.1136/annrheumdis-2019-215213. Recurrent Venous Thromboembolism in Older Patients? Am J 27. Lopes MRU, Danowski A, Funke A, Rêgo J, Levy R, An- Med. 2017 Oct;130(10):1220.e17-1220.e22. doi: 10.1016/j.am- drade DCO. Update on antiphospholipid antibody syndrome. jmed.2017.05.026. Rev Assoc Med Bras (1992). 2017 Nov;63(11):994-999. doi: 14. Chiasakul T, De Jesus E, Tong J, Chen Y, Crowther M, 10.1590/1806-9282.63.11.994. Garcia D, Chai-Adisaksopha C, Messé SR, Cuker A. Inherit- 28. Svenungsson E, Antovic A. The antiphospholipid syndrome ed Thrombophilia and the Risk of Arterial Ischemic Stroke: A - often overlooked cause of vascular occlusions? J Intern Med. Systematic Review and Meta-Analysis. J Am Heart Assoc. 2019 2020 Apr;287(4):349-372. doi: 10.1111/joim.13022. Oct;8(19):e012877. doi: 10.1161/JAHA.119.012877. 29. Thomas RH. Hypercoagulability syndromes. Arch Intern Med. 15. Corral J, de la Morena-Barrio ME, Vicente V. The genetics of 2001 Nov 12;161(20):2433-9. doi: 10.1001/archinte.161.20.2433. antithrombin. Thromb Res. 2018 Sep;169:23-29. doi: 10.1016/j. 30. Healy B, Levin E, Perrin K, Weatherall M, Beasley R. Pro- thromres.2018.07.008. longed work- and computer-related seated immobility and risk of

42 RADIOLOGY UPDATE VOL. 5 (8) ISSN 2424-5755

venous thromboembolism. J R Soc Med. 2010 Nov;103(11):447- crinol Metab. 2009;94(9):3171–82. 54. doi: 10.1258/jrsm.2010.100155. 47. Randeria SN, Thomson GJA, Nell TA, Roberts T, Pretorius E. 31. Blokhin IO, Lentz SR. Mechanisms of thrombosis in obesi- Inflammatory cytokines in type 2 diabetes mellitus as facilitators ty. Curr Opin Hematol. 2013 Sep;20(5):437-44. doi: 10.1097/ of hypercoagulation and abnormal clot formation. Cardiovasc MOH.0b013e3283634443. Diabetol [Internet]. 2019;18(1):72. Available from: https://doi. 32. Vilahur G, Ben-Aicha S, Badimon L. New insights into the org/10.1186/s12933-019-0870-9. role of adipose tissue in thrombosis. Cardiovasc Res. 2017 Jul 48. Caine GJ, Stonelake PS, Lip GYH, Kehoe ST. The hyperco- 1;113(9):1046-1054. doi: 10.1093/cvr/cvx086. agulable state of malignancy: Pathogenesis and current debate. 33. Iba T, Levi M, Levy JH. Sepsis-Induced and Neoplasia. 2002;4(6):465–73. Disseminated Intravascular Coagulation. Semin Thromb He- 49. Dearborn JL, Urrutia VC, Zeiler SR. Stroke and Can- most. 2020 Feb;46(1):89-95. doi: 10.1055/s-0039-1694995. cer- A Complicated Relationship. J Neurol Transl Neurosci. 34. Simmons J, Pittet JF. The coagulopathy of acute sepsis. 2014;2(1):1039. Curr Opin Anaesthesiol. 2015 Apr;28(2):227-36. doi: 10.1097/ 50. Dardiotis E, Aloizou AM, Markoula S, Siokas V, Tsarou- ACO.0000000000000163. has K, Tzanakakis G, et al. Cancer-associated stroke: Patho- 35. Levi M, van der Poll T. Coagulation and sepsis. Thromb Res. physiology, detection and management (Review). Int J Oncol. 2017 Jan;149:38-44. doi: 10.1016/j.thromres.2016.11.007. 2019;54(3):779–96. 36. Levi M, Schultz M, van der Poll T. Sepsis and thrombosis. 51. Wu N, Tong S, Xiang Y, Wu L, Xu B, Zhang Y. Association Semin Thromb Hemost. 2013 Jul;39(5):559-66. doi: 10.1055/s- of Hemostatic Markers with Atrial Fibrillation : A Meta-Analysis 0033-1343894. and Meta- Regression. 2015;1–19. 37. Parra-Izquierdo I, Aslan JE. Perspectives on Platelet Heter- 52. Watson T, Shantsila E, Lip GYH. Mechanisms of throm- ogeneity and Host Immune Response in Coronavirus Disease bogenesis in atrial fibrillation : Virchow ’ s triad revisited. Lancet 2019 (COVID-19). Semin Thromb Hemost. 2020;46(7):826–30; [Internet]. 2009;373(9658):155–66. Available from: http://dx.doi. org/10.1016/S0140-6736(09)60040-4 38. Panigada M, Bottino N, Tagliabue P, Grasselli G, Novembri- no C, Chantarangkul V, et al. Hypercoagulability of COVID-19 53. Danese E, Montagnana M, Cervellin G, Lippi G, Danese E, patients in intensive care unit: A report of thromboelastography Montagnana M, et al. Annals of Medicine Hypercoagulability findings and other parameters of hemostasis. J Thromb Haemost. , D-dimer and atrial fibrillation : an overview of biological and 2020;18(7):1738–42. clinical evidence. 2014;3890. 39. Yan Zhang, M.D. Meng Xiao, M.Sc. Shulan Zhang, M.D. Peng Xia MD, Wei Cao MD, Wei Jiang MD, Huan Chen MD, Xin Ding MD, Hua Zhao, M.D. Hongmin Zhang MD. Correspondence Coagulopathy and Antiphospholipid Antibodies in Patients with Covid-19. Nejm. 2020;38(1):1–3. 40. Helms J, Tacquard C, Severac F, Leonard-Lorant I, Ohana M, Delabranche X, et al. High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective co- hort study. Intensive Care Med [Internet]. 2020;46(6):1089–98. https://doi.org/10.1007/s00134-020-06062-x. 41. Han H, Yang L, Liu R, Liu F, Wu K, Li J, Liu X, Zhu C. Prom- inent changes in blood coagulation of patients with SARS-CoV-2 infection. Clinical Chemistry and Laboratory Medicine (CCLM). 2020;58(7): 1116-1120. https://doi.org/10.1515/cclm-2020-0188. 42. Wiese OJ, Allwood BW, Zemlin AE. COVID-19 and the re- nin-angiotensin system (RAS): A spark that sets the forest alight? Med Hypotheses [Internet]. 2020;144(September):110231. Avail- able from: https://doi.org/10.1016/j.mehy.2020.110231. 43. Remková A, Remko M. The role of renin-angiotensin system in prothrombotic state in essential hypertension. Physiol Res. 2010;59(1):13–23. 44. Domingueti CP, Dusse LMSA, Carvalho MDG, De Sousa LP, Gomes KB, Fernandes AP. Diabetes mellitus: The linkage between oxidative stress, inflammation, hypercoagulability and vascular complications. J Diabetes Complications [Internet]. 2016;30(4):738–45. Available from: http://dx.doi.org/10.1016/j. jdiacomp.2015.12.018. 45. Pretorius L, Thomson GJA, Adams RCM, Nell TA, Laubscher WA, Pretorius E. Platelet activity and hypercoagulation in type 2 diabetes. Cardiovasc Diabetol [Internet]. 2018;17(1):141. Availa- ble from: https://doi.org/10.1186/s12933-018-0783-z. 46. Goldberg RB. Cytokine and cytokine-like inflammation markers, endothelial dysfunction, and imbalanced coagulation in development of diabetes and its complications. J Clin Endo-

43